CLENTIAZEM, DILTIAZEM, AND COLD CARDIOPLEGIA IN ISOLATED ISCHEMIC RABBIT HEARTS - RELATION BETWEEN ADDITIVE CARDIOPROTECTION, PHYSICOCHEMICAL PROPERTIES, AND PRESERVATION OF MYOCARDIAL LIPID COMPONENTS

Diltiazem is known to exert significant cardioprotection, but its effi cacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chl orobenzothiazepine derivative of diltiazem, may offer cytoprotection a dditive to cold cardioplegia. We investigated the cardioprotective act ions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to c old cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Function al recovery was assessed by measuring left ventricular developed press ure (LVDP), coronary flow (CF) and heart rate (HR). To explore the pot ential beneficial mechanisms of these agents, we measured myocardial l ipids and total calcium at the end of a 30-min period of reperfusion a s well as their myocardial accumulation. Addition of 10(-8) M clentiaz em to cold cardioplegia resulted in significant improvement in mechani cal recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postisc hemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a hi gher concentration (10(-6) M) and these effects were correlated with m yocardial accumulation of the drug. The additive cardioprotective effe ct of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in additi on to cold cardioplegia. These results indicate that the additive card ioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-i nduced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery . The functional protection offered by 10(-8) M clentiazem was associa ted with preservation of myocardial lipid components. Myocardial chole sterol content, which is essential for maintenance of membrane integri ty, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Tota l myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduc tion in plasmalogen content, the predominant myocardial phospholipid s pecies, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepin es, suggesting that cold cardioplegia is sufficient to prevent irrever sible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia. Its effectiveness apparently is related to some ph ysicochemical properties, its coronary vasodilator action, and direct cytoprotection through preservation of essential myocardial lipid comp onents.